Pathophysiology Of Alcoholic Liver Disease Research Articles

From Alcohol Toxicity to Treatment

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. This symposium was dedicated to Charles S. Lieber in recognition of his contribution in alcohol research over the last 50 years. It was divided into two parts, namely effects of alcohol on the gastrointestinal tract and effects of alcohol on the liver. Major emphasis was given to recent discoveries elucidating mechanisms of alcohol-associated carcinogenesis. M. Salaspuro (Finland) discussed the role of acetaldehyde in the saliva and in the large intestine with respect to its role in the pathogenesis of alcohol-associated cancer, and H. K. Seitz (Germany) presented new data identifying individuals homozygous for the ADH1C&1 allele as high on risk for alcohol-associated upper aerodigestive tract cancer. M. Savolainen (Finland) discussed the role phosphatidylethanol as a bioactive lipid that can mediate beneficial and harmful effects of alcohol drinking. In the second part of the symposium, alcoholic liver disease was discussed. P. Haber (Australia) presented new data on hepatic transcriptome in alcoholic liver disease with the identification of new genes possibly involved in alcohol-initiated fibrogenesis of the liver, and H. Moshage (The Netherlands) described survival mechanisms of the cholestatic hepatocytes with implications for therapy in cholestatic liver disease. The role of the hepatic microsomal ethanol oxidizing system in the metabolism of alcohol in alcoholic liver disease was summarized by R. Teschke (Germany). H. Ishii (Japan) discussed the current status and treatment of alcoholic hepatitis in Japan. Finally, in a state-of-the-art lecture, Charles S. Lieber (USA) discussed the development of the understanding of the pathophysiology of alcoholic liver disease in the last 50 years. He emphasized the role of pathophysiology as an important prerequisite for better treatment strategies.

Alcoholic Liver Disease: From Pathophysiology to Therapy

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. A salient feature of this symposium was to demonstrate how the striking advances made in our understanding of the pathophysiology of alcoholic liver disease are now raising prospects for better treatment as well. Genetic factors are now being elucidated, and F. Stickel (Germany) has summarized his own studies as well as those of others. M. Salaspuro (Finland) updated the possible role of gut bacteria in the pathogenesis of alcoholic liver disease, bringing us closer to antibacterial therapy as part of the treatment of alcoholic liver disease. Specifically, the gut bacterial flora may be important via the in situ production of acetaldehyde and the associated intestinal injury, which may favor the translocation of toxins from the gut lumen to the systemic circulation and the liver. The analytical progress in the assessment of alterations of phospholipid composition in liver membranes described by H. P. Schlemmer (Germany) may eventually give us an objective method to recognize patients in whom phospholipid therapy might be indicated. Other novel treatment modalities for severe alcoholic hepatitis were described by Y. Horie and H. Ishii (Japan), including plasma exchange. Finally, the pros and cons of nutraceutical therapy were analyzed by C. S. Lieber, with a demonstration that although some nutraceuticals may have toxicity exacerbated by alcohol and must be administered very carefully within a narrow therapeutic window, others are actually beneficial as demonstrated under controlled conditions.

Nouveaux traitements de l'hépatite alcoolique aiguë

Alcoholic hepatitis is a common disease with an overall 1-year mortality of 20 %. Although the classical treatment for alcoholic hepatitis is abstinence, in some individuals abstinence alone is inadequate to promote survival and recovery. This is particularly true of patients with severe alcoholic hepatitis. Several agents have been examined as treatments for alcoholic hepatitis and cirrhosis. They have targeted several key processes in the pathophysiology of alcoholic liver disease, including hypermetabolism, inflammation, cytokine dysregulation and oxidant stress. The compounds that offer the greatest survival benefit to patients with severe alcoholic hepatitis are corticosteroids. But positive results are not uniform and there remains some controversy over their efficacy. Even if corticosteroids are beneficial for alcoholic hepatitis, they are not recommended for all patients at risk. In this regard other agents are being tested : pentoxifylline shows some promise, as does enteral feeding with medium chain triglycerides. Independent efforts are also being directed toward treatment of inflammation injuries of chronic alcoholic liver disease and alcoholic cirrhosis, anti-oxidants and anti-tumour necrosis factor alpha have received the greatest attention. Liver transplantation is sometime the only treatment of severe acute alcoholic hepatitis.

Treatment of alcoholic hepatitis.

Alcoholic hepatitis is a common disease with an overall 1-year mortality of 20%. Although the classical treatment for alcoholic hepatitis is abstinence, in some individuals abstinence alone is inadequate to promote survival and recovery. This is particularly true of patients with severe alcoholic hepatitis, who are identified by jaundice, coagulopathy and neutrophilia. Within the last two decades, several agents have been examined as treatments for alcoholic hepatitis and cirrhosis. They have targeted several key processes in the pathophysiology of alcoholic liver disease, including hypermetabolism, inflammation, cytokine dysregulation and oxidant stress. The compounds that offer the greatest survival benefit to patients with severe alcoholic hepatitis are corticosteroids. Several groups have reported excellent results with corticosteroids, but positive results are not uniform, and there remains some controversy over their efficacy. Even if corticosteroids are beneficial for alcoholic hepatitis, they are not recommended for all patients at risk. Consequently, other agents are being tested that have broader applicability to individuals with contraindications to steroids. In this regard, pentoxifylline shows some promise, as does enteral feeding with medium chain triglycerides. Independent efforts are also being directed toward treatment of chronic alcoholic liver disease and alcoholic cirrhosis. Anti-oxidants have received the greatest attention; drugs such as S-adenosyl-methionine may be of benefit. This and others are under active study.

Scanning Electron Microscopic Studies on Morphological Abnormalities of Erythrocytes in Alcoholic Liver Diseases

We previously reported that morphological abnormalities and the altered deformability of erythrocytes play important roles in disturbances of hepatic microcirculation associated with alcoholic liver disease. The subjects of this study were five patients with alcoholic liver cirrhosis, two patients with alcoholic fatty liver, and two healthy volunteers. Concentrating on erythrocyte morphology in the presence of alcoholic liver disease, we observed erythrocytes under a scanning electron microscope and examined their morphological changes in relation to the disease. Among the five patients with alcoholic liver cirrhosis, stomatocytes accounted for about 14% and acanthocytes for about 10% of all erythrocytes. In the fatty liver group (n = 2), acanthocytes were absent, and stomatocytes accounted for 23% in one subject and 56% in the other, of the total. When the two patients with liver cirrhosis were examined over time, one of them was found to have 12% stomatocytes, 21% acanthocytes, and a filtration time of 14.7 sec at admission. Following 1 month of abstinence, this patient had 1% stomatocytes, 6% acanthocytes, and a filtration time of 10.4 sec, which were accompanied by improvements in peripheral blood parameters and liver function. In another patient with liver cirrhosis, there were no acanthocytes, 8% stomatocytes, and a filtration time of 5 sec at admission; this patient had 1% stomatocytes and a filtration time of 7.7 sec after 1 month of abstinence. In one patient with fatty liver who was examined over time, the percentage of stomatocytes was 56%, and the filtration time was 7.7 sec at admission; these parameters were 1% and 5.1 sec, respectively, after 1 month of abstinence. The present study revealed that stomatocytes and acanthocytes are morphologically abnormal erythrocytes observed in the presence of alcoholic liver disease. These abnormal forms of erythrocytes tended to normalize as peripheral blood parameters and liver function were improved by abstinence, which suggests that erythrocyte morphology is related to the pathophysiology of alcoholic liver disease.

Role of Kupffer Cell‐Derived Reactive Oxygen Intermediates in Alcoholic Liver Disease in Rats In Vivo

The pathophysiology of alcoholic liver disease (ALD) remains largely unknown. In this work, we have developed an experimental rat model to elucidate the mechanism of liver injury, including ALD, in which Kupffer cell-derived reactive oxygen intermediates (ROIs) might be involved. Groups of male Wistar rats were pair-fed on a liquid high-fat diet containing ethanol (36% of total calories) or isocaloric carbohydrate with or without dietary carbonyl iron (0.5% w/v) for 3 weeks. In this rat model, we investigated Kupffer cell-derived ROI generation, which affected hepatocellular injury and hepatic fibrosis in ALD. The production of ROIs in Kupffer cells isolated from the iron-fed, the ethanol-fed, and the ethanol plus iron-fed rats were significantly increased, compared with that in Kupffer cells isolated from control rats (iron > ethanol+iron > ethanol > > control). However, hepatic vitamin E content in the ethanol plus iron-fed rats was decreased rather than that in the iron-fed rats. Then, lipid peroxidation of isolated microsomes was assessed as malondialdehyde equivalents determined by thiobarbituric acid assay. Compared with controls, the malondialdehyde equivalents were elevated in experimental groups (ethanol+iron > ethanol > iron > control). Serum ALT levels were greatly elevated in rats fed a diet containing both ethanol and iron (ethanol+iron > iron > ethanol > control). Hepatic content of hydroxyproline was significantly increased in ethanol plus iron-fed rats, compared with rats other than the ethanol plus iron-fed group (ethanol+iron > iron > ethanol > control). These results suggested that the enhanced Kupffer cell-derived ROI generation could itself contribute to the increased susceptibility to lipid peroxidation, which might cause hepatocellular injury and lead to hepatic fibrosis in ALD.

Role of Kupffer Cell-Derived Reactive Oxygen Intermediates in Alcoholic Liver Disease in Rats In Vivo

The pathophysiology of alcoholic liver disease (ALD) remains largely unknown. In this work, we have developed an experimental rat model to elucidate the mechanism of liver injury, including ALD, in which Kupffer cell-derived reactive oxygen intermediates (ROIs) might be involved. Groups of male Wistar rats were pair-fed on a liquid high-fat diet containing ethanol (36% of total calories) or isocaloric carbohydrate with or without dietary carbonyl iron (0.5% w/v) for 3 weeks. In this rat model, we investigated Kupffer cell-derived ROI generation, which affected hepatocellular injury and hepatic fibrosis in ALD. The production of ROIs in Kupffer cells isolated from the iron-fed, the ethanol-fed, and the ethanol plus iron-fed rats were significantly increased, compared with that in Kupffer cells isolated from control rats (iron > ethanol + iron > ethanol ≫ control). However, hepatic vitamin E content in the ethanol plus iron-fed rats was decreased rather than that in the iron-fed rats. Then, lipid peroxidation of isolated microsomes was assessed as malondialdehyde equivalents determined by thiobarbituric acid assay. Compared with controls, the malondialdehyde equivalents were elevated in experimental groups (ethanol + iron > ethanol > iron > control). Serum ALT levels were greatly elevated in rats fed a diet containing both ethanol and iron (ethanol + iron > iron > ethanol > control). Hepatic content of hydroxyproline was significantly increased in ethanol plus iron-fed rats, compared with rats other than the ethanol plus iron-fed group (ethanol + iron > iron > ethanol > control). These results suggested that the enhanced Kupffer cell-derived ROI generation could itself contribute to the increased susceptibility to lipid peroxidation, which might cause hepatocellular injury and lead to hepatic fibrosis in ALD.

Treatment of alcoholic liver disease

With advances in our understanding of the pathophysiology of alcoholic liver disease, pharmacological treatments of some of the basic disease processes are now in sight. The most notable development has been the introduction of propylthiouracil for the treatment of alcoholic hepatitis. In a recent trial the mortality rate of patients treated with this drug was 62% lower than that of a control group. Its beneficial effects may stem not from its anti-thyroid properties but rather from other actions such as free radical scavenging. Corticosteroids now appear to have no place in the treatment of alcoholic liver disease. Anabolic steroids, however, show promise, though longer term trials are required before this can be confirmed. Colchicine, too, has been reported to improve survival in patients with established cirrhosis. More experience is required with this and other anti-inflammatory and anti-fibrogenic drugs. β Adrenergic blocking drugs, such as propranolol, reduce portal venous pressure. In a trial among patients with alcoholic cirrhosis who had oesophageal varices, 39% of those receiving propranolol had not experienced a haemorrhage by 2 years compared with 74% in the control group. The mortality rates at this time were 28% and 49% respectively. Results of treatment once the first haemorrhage has occurred are less impressive. Treatment of the alcohol withdrawal syndrome in patients with liver disease is often problematic. The dose of any sedative should be reduced to 25–50% of the usual dose and sedatives should be avoided in patients who are encephalopathic. Once the patient has recovered from the acute illness, abstinence from alcohol remains the single most important factor that determines long term survival.

Pathophysiology of alcoholic liver disease

Pathophysiology of alcoholic liver disease